Investigation has focused on the regulation and actions of cortiocotropin releasing factor receptors and the interactions of CRF with other ACTH regulators. A. CRF receptor regulation. We have previously shown that pituitary receptor downregulation and desensitization that accompany the increase in plasma ACTH often adrenalectomy is partially due to increased hypothalamic CRF secretion. Studies in rats with hypothalamic lesions demonstrated that the effect of adrenalectomy is completely dependent on hypothalamic factors. Glucocorticoid deficiency per se is not involved since physiological amounts of corticosterone decrease CRF receptors. Desensitization of plasma ACTH responses during prolonged stress is accompanied by CRF receptor downregulation and desensitization of cAMP responses to CRF. However, pituitary responsiveness in vivo is maintained or increased probably due to spared/CRF receptors and other regulators, mainly VP. Brain CRF receptoors were unchanged during glucocorticoid administration and stress. B. Mechanisms of action and interaction between ACTH regulators. Previous studies have shown that the effect of CRF is cAMP dependent while other stimuli increase ACTH secretion and potentiate the simulation by CRF through calcium/phospholipid dependent mechanisms, with activation of protein kinase C. Further studies demonstrated that potentiation of CRF action by VP involves enhancement of CRG stimulated cAMP levels due to inhibition of phosphodiesterase, and protein kinase C dependent phosphorylation of a component of adenylate cyclase. Regulation of corticotroph function also involves dual effects of arachidonic acid metabolites, with lipooxygenase and cyclooxygenase products being stimulatory and inhibitory, respectively. Kinetic studies in cultured pituitary cells showed two phases of ACTH secretion by CRF and cAMP independent stimuli; an early phase with a rapid increase in ACTH release rate which is independent of extracellular calcium, and a late phase of constant secretion rate with partial calcium dependence for CRF, and complete calcium dependence for non-cAMP dependent stimuli.